Many women experience unintended pregnancy as a result of either a lack of preparedness or contraceptive failure. Emergency contraception (EC) is an effective option after unprotected intercourse to prevent an unwanted pregnancy. Ulipristal acetate (UPA), also referred to as VA/CDB-2914, is the first progesterone receptor (PR) modulator that has been developed for emergency contraception (EC). Our recent studies have shown that UPA prevents ovulation by blocking the PR-dependent pathways that are intrinsic to ovary. Although UPA is effective in EC when the time of its administration immediately precedes or follows the luteinizing hormone (LH) surge, it becomes less effective in blocking ovulation once a few hours have elapsed after the surge and PR signaling is well underway. It is our hypothesis that a drug that inhibits the activity of a critical regulator of follicular rupture will be able to prevent ovulation even after the onset of PR signaling following the LH surge, thus increasing the window of effect for EC. In an effort to identify such targets, we have begun our work with the mouse model, which exhibits remarkable similarity to the human in the hormonal regulation ofthe ovulatory process. Our studies revealed that endothelin-2 (ET-2), a potent vasoactive molecule, is dramatically and transiently induced in mural granulosa cells of the preovulatory follicles immediately preceding ovulation. Most importantly, our preliminary studies showed that blockade of endothelin signaling by administration of antagonists of endothelin receptor types A and B, at a time period when UPA is no longer effective, is able to prevent follicular rupture. These exciting results prompt us to propose the following aims. Aim 1: Determine the effectiveness of antagonists of endothelin receptors (AETRs) as a blocker of ovulation. Aim 2: Determine the effects of AETRs on follicular functions, and Aim 3:Analyze the mechanism of action of AETRs as a suppressor of ovulation. Collectively, the studies proposed in this application will yield significant and novel findings that will not only advance our understanding of ovarian physiology during ovulation but also provide new leads for development of next generation EC agents.